Sensitivity Analysis of a Physiologically Based Pharmacokinetic Model Used for Treatment Planning in Peptide Receptor Radionuclide Therapy

Abstract

The aim of this work was to evaluate the sensitivity of time-integrated activity coefficients (TIACs) on the erroneously chosen prior knowledge in a physiologically based pharmacokinetic (PBPK) model used for treatment planning in peptide receptor radionuclide therapy (PRRT). Parameters of the PBPK model were fitted to the biokinetic data of 15 patients after the injection of (111)In-DTPAOC. The fittings were performed using fixed parameter values taken from literature as prior knowledge (reference case, Ref). The fixed parameters were gender, physical information (e.g., body weight), dissociation rate koff, dissociation constant KD, fraction of blood flow, and spleen and liver volumes. The fittings were repeated with changed fixed parameters (Changed). The relative deviations (RDs) of TIACs calculated from Changed and Ref were analyzed for kidneys, tumor, liver, spleen, remainder, whole body, and serum. A changed koff has the largest effect on RD, the largest RD values were found for changed koff = 0.001 L/min: RDkidneys = (3 ± 3)%, RDtumor = (0.5 ± 4)%, RDliver = (6 ± 9)%, RDspleen = (5 ± 5)%, RDremainder = (2 ± 31)%, RDserum = (-4 ± 25)%, and RDwholebody = (3 ± 16)%. For other changed parameters, the maximum RDs were <1%. The calculation of organ TIACs in PRRT using the PBPK model was little affected by assigning wrong prior knowledge to the evaluated patients. The calculation of bone marrow-absorbed doses could be affected by the inaccurate TIACs of serum and remainder in the case of an inadequate koff.

Important pharmacokinetic parameters for individualization of 177Lu‐PSMA therapy: A global sensitivity analysis for a physiologically‐based pharmacokinetic model

“…The latter were obtained from the fit of the PBPK model to individual biokinetic data. Our previous study showed a marginal effect of changed fixed parameters to the estimation of individual TIACs 25 . Therefore, in this study, we investigated the effect of the interindividual variability of the estimated parameters (Table I) on the variability of the ADs in 177 Lu‐labeled PSMA‐targeting radioligand therapy using a GSA and a PBPK model.…”

“…18,19,24 The PBPK model for the 177 Lu-labeled PSMA-targeting radioligand therapy contains many fixed parameters that have been shown to have a marginal effect to the estimation of individual TIACs. 25 Therefore, the input of interest, as the subject of the GSA analysis, are those parameters which have been estimated from the biokinetic data of the patient population. 18 The list of the investigated parameters in this study is shown in Table I.…”

“…Clearly, this is not the case, however, we have shown earlier a marginal effect of changed fixed parameters to the TIACs due to the fitting of the individual parameters. 25 5. The population used for the definition of the parameter distribution is relatively small (n = 13).…”

Time‐integrated activity coefficient estimation for radionuclide therapy using PET and a pharmacokinetic model: A simulation study on the effect of sampling schedule and noise

“…Recently it has been shown that the determination of TIACs is little affected by some erroneously chosen fixed parameters for this PBPK model. 50 Nevertheless, the quality of some fixed parameters which are taken from previous studies should be improved to increase the accuracy of the TIAC determination. For example, using measured dissociation rates k off for each substance instead using k off derived from DOTA-RGD for all substances.…”

Treatment planning in PRRT based on simulated PET data and a PBPK model

“…PBPK models have been proven to be a powerful method to analyse, simulate and predict the biodistribution of radiolabelled substances (10)(11)(12)(13)(14)(15)(16)(17)(18). The effect of different biodistributions during pre-therapeutic and therapeutic stage can be included in the PBPK model.…”